Stable heteroatomic mercuri mercapto compounds and water soluble salts thereof



Patented Oct. 17, 1939 UNITED STATES PATENT OFFICE STABLE HETEROATOMICMERCURI MER- CAPTO COMPOUNDS AND WATER SOLU- BLE SALTS THEREOF Russel J.Fosbinder, Short Hills, and Lewis A. Walter, East Orange, N. J.,assignors to The Maltbie Chemical Company, Newark, N. J., a corporationof New Jersey No Drawing. Application September 15, 1937, Serial No.163,956

8 Claims. (Cl. 260-270) This invention relates to organic mercurycompounds useful as antiseptics, germicides and bactericides, and, moreparticularly, to mercurimercapto compounds of that character. A

principal object of the invention is to provide ever, most meroaptocompounds are susceptible 5 new and useful compounds of the typeindicated, to oxidation by oxygen,so much so that the and which areeither themselves water-soluble, or presence of even a very minuteamount of a which have water-soluble salts, or both, and metallic ioncatalyst, particularly the copper ion,

I which are stable toward oxidation by oxygen, but also manganese orothers, results in rapid 10 even in the presence of metal ion catalysts.deterioration of the compound, with resulting Another object of theinvention is to provide less of antiseptic efiiciency and otherundesiranew and useful water soluble salts, such as the ble propertiesof the deteriorated or oxidized maalkali metal and ammonium salts, andthe alkylterial. In the past, this susceptibility to oxidaamine saltsand alkanolamine salts, of such comtion and deterioration has seriouslyaffected the pounds, which salts, in water solution of suitableusefulness of mercuri-mercapto compounds when 15 concentration, havenovel and valuable bacterisought to be used as antiseptics, since byreason cidal and antiseptic properties. of the dilution required intherapeutic applica- Still another object of the invention is the tions(necessitated by the relatively high toxicity provision of certain newand useful antiseptic, of the mercury), and the alkalinity of thesolugermicidal and bactericidal alkyl-mercuri-mertion necessary toprevent precipitation of the 20 capto compounds containing aheteroatomic'rin corresponding acid compound, the deterioration havingone nitrogen atom, the other atoms of the is marked and rapid eventhough the content ring being carbon, the alkyl-mercuri radical of ofcopper ions in the solution is as little as one the compound beinglinked to one of the carbon part in one million; while other metal ioncataatoms of the ring through a sulfuratom, said lysts are almostequally deleterious. Further, it 25 compounds being stable toward freeoxygen even is impractical, if not actually impossible to preatrelatively elevated temperatures and even in pare such compounds andtheir solutions entirely the presence of metal ion catalysts. Suchcomfree from copper, while manganese and iron, also pounds are also,preferably, provided with an diflicult to eliminate, also causedeterioration,

50 acidic group attached to still another carbon although to a somewhatless degree. atom of the ring by replacement of a hydrogen The presentinvention, however, provides a atom, in order to impart water solubleproperties class or series of new and useful mercurito the salts of thecompound, and such acidic mercapto compounds which are not only activegroup is, in the preferred compounds, a carand effective as antisepticsand bactericides, but

boxylic group. which are also stable against oxidation by 35 A stillfurther object of the invention is the oxygen, even in the co-presenceof metallic ion provision of new and useful water-soluble saltscatalysts such as copper, iron and manganese, of the foregoingcompounds, exemplified by the and even at relatively elevatedtemperatures. alkali-metal, ammonium, and alkylamine and The newcompounds which we have discovered,

lo alkanolamine salts thereof, which salts have exand which form thesubject-matter of this applicellent new and useful antiseptic,germicidal and cation for patent, are of the general formulabactericidal properties when employed in aqueous Rr-HgS-R in which Rrepresents an alkyl solutions of suitable concentration. radical; Hg,mercury; S, sulfur; and R a six- Other objects of the invention willappear from membered unsaturated heteroatomic ring conthe followingdescription. taming one nitrogen atom and five carbon atoms,

Mercuri-mercapto compounds are desirable as and linked to the RHg groupthrough the antiseptics and germicides for many purposes, by sulfuratom, which latter is attached to a carbon reasonof the fact that themercapto group tends atom of the ring by replacement of a hydrogen toinduce increased cell proliferation, and variatom. Water-solubility isimparted to the comous compounds of that type have been used or pound byreplacing an additional hydrogen atom 50 proposed in medicine to promotethe healing of by an acidic group, preferably a carboxylic radiwounds',ulcers, and open infections or the like. cal, which is capable offorming water-soluble On the other hand, mercury tends to exert a toxicsalts of the compound by replacement of the effect on theregeneration oftissue. Hence, by hydrogen atom of the acidic or carboxyl group.

combining the two effects it hasbeen attempted Ordinarily, the compoundsthemselves are not 55 water soluble, although they may be used asgermicides in alcoholic or other suitable nonaqueous solution; however,we ordinarily prefer to prepare the water-soluble salts, such as alkalimetal, ammonium, or alkylamine or alkanolamine salts thereof, or evenalkaline-earth metal salts thereof, and to employ the same asantiseptics in water solution of suitable concentration.

Compounds of the above type may be suitably prepared by refluxing amercapto-pyridine carboxylic acid, in alcohol, as ethyl alcohol, orother suitable solvent, and an ethyl, propyl, butyl or like mercuricchloride, followed by recovery of the resulting alkylmercuri-thiopyridine carboxylic acid, as will now be shown in greaterdetail by the following specific examples.

EXAMPLE 1 An example illustrative of a suitable method for preparationof a preferred type of compound according to our invention is asfollows:

2-ethylmercuri thiopyridine 5-CaTbOIIZI/1Zic acid 7.8 grams ofZ-mercapto pyridine fi-carboxylic acid, 50 cc. of twice normal causticsoda solution, 500 cc. of ethyl alcohol, and 13.4 grams of ethylmercuric chloride are refluxed together for one hour. The solution isthen concentrated to about half the original volume, and then dilutedwith water to approximately the original volume. Any unreacted ethylmercuric chloride is thus precipitated out of the solution. The dilutedsolution is then cooled, filtered, and the filtrate is acidified 1: withacetic acid until precipitation of the alkyl mercury compound isobtained. The resulting precipitate is removed by filtration andrecrystallized from alcohol. The resulting compound 2- ethylmercurithiopyridine 5-carboxy1ic acid, is in the form of white crystals,softening at about 210 C., and gradually decomposing at from about250-300 C.

An analysis of the resulting compound was found to give a mercurycontent of 52.14%, whereas the theoretical mercury content for2-ethylmercuri thiopyridine 5-carboxylic acid is 52.22%, showing thatthe preparation of the compound according to the foregoing exampleresults in the production of substantially pure 2-ethylmercurithiopyridine 5-carboxylic acid.

The structural formula of the compound is believed to be as follows,according to our determinations:

While the foregoing compound may be utilized for its germicidalproperties, as in alcoholic or other suitable non-aqueous solution, weprefer to use the compound in water-soluble form, to which end a salt ofthe compound, rendering it watersoluble, is prepared. Thus a sodium saltof the above compound, suitable for pharmaceutical and medicinal use,may be prepared by dissolving one molecular equivalent of the mercurycompound (Z-ethylmercuri thiopyridine 5-carboxylic acid) in a moderatelyconcentrated solution containing one molecular equivalent of sodiumhydroxide,

. and then precipitating the solution of the salt with ethyl alcohol,filtering and drying.

The resulting sodium salt is Water soluble and may be dissolved in waterand used for its germicidal or antiseptic properties in suitableconcentrations; for example a water solution having a concentration of 1part of the salt to 1000 parts of water has been found to have excellentgermicidal properties.

The ammonium salt of 2-ethylmercuri thiopyridine 5-carboxylic acid maybe prepared by dissolving one molecular equivalent of the mercurycompound (2-ethylmercuri thiopyridine 5- carboxylic acid) in amoderately concentrated solution containing one molecular equivalent ofammonium hydroxide. The salt is then precipitated from the aqueoussolution by a suitable nonaqueous solvent, filtered and dried.

The resulting ammonium salt may be dissolved in water and used as agermicide at approximately the same concentration as the sodium salt.

Other salts which have been found particularly desirable for variousgermicidal purposes, both because of their pharmaceutical compatibilityand broad range of water-solubility, are the alkylamine salts and thealkanolamine salts.

A particular example is the ethanolaminesalt having a structural formulawhich we have found The alkylamine salts of 2-ethylmercuri thiopyridine5-carboxylic acid may be prepared, in

general, by dissolving one molecular equivalent of the mercury compoundin a moderately concentrated solution containing one molecularequivalent of the alkylamine.

The ethanolamine salt may be prepared as follows: Dissolve one molecularequivalent of v 2- ethylmercuri thiopyridine 5-carboxylic acid in amoderately concentrated solution containing one molecular equivalent ofethanolamine. The re sulting solution may be used in suitableconcentrations, as before.

Further examples of the preparation of compounds according to ourinvention are as follows:

EXAMPLE 2 V 2 n-propylmercuri thiopyridine 5ca1b0wylz'c acid Thiscompound may be prepared as follows:

'1 .8' grams of Z-mercapto pyridine 5-carboxylic acid, 50 cc. of twicenormal caustic soda solution, 500 cc. of ethyl alcohol, and 13.5 gramsof n-propyl mercuric chloride are refluxed together for one hour. Thesolution is concentrated to about half the original volume and dilutedwith water t approximately the original volume. This solution is cooled,filtered, and the filtrate acidified with acetic acid. The resultingprecipitate isremoved by filtration and recrystallized from alcohol. Theresulting compound is found to have the form of white crystalsdecomposing at 205- 210 C. with evolution of gas.

An analysis of the resulting compound was found to give a mercurycontent of 50.28%, whereas the theoretical mercury content for 2n-propylmercuri thiopyridine 5-carboxylic' acid is 50.37%, showing thatthe preparation of the compound according to the foregoing exampleresults in the production of'substantially pure 2 n-propylmercurithiopyridine 5-carboxylic acid.

Aqueous solutions of the various water-soluble salts of the 2n-propylmercuri thiopyridine 5- carboxylic acid resulting from theforegoing procedure may be prepared in manner similar to the directionsgiven in Example 1, and employed in suitable concentrations.

Still another example of the preparation of compounds according to ourinvention is as follows:

EXAMPLE 3 2 n-butylmercuz' thiopyridine 5-carboxylic acid 7.8 grams of2-mercapto pyridine 5-carboxylic acid, 50 cc. of twice normal causticsoda solution, 500 cc. of ethyl alcohol, and 14 grams of n-butylmercuricchloride are refluxed together for one hour. The solution is thenconcentrated to about one-half the original volume, and then dilutedwith water to approximately the original volume. This solution ischilled, filtered, and the filtrate acidified with acetic acid. Theresulting precipitate is recrystallized from alcohol. The resultingwhite crystals are found to decompose at about 185-190" C. with theevolution of gas.

An analysis of the resulting compound was found to give a mercurycontent of 48.42%, Whereas the theoretical mercury content for 2n-butylmercuri thiopyridine 5-carboxylic acid is 48.69%, showing thatthe preparation of the compound according to the foregoing exampleresults in the production of substantially pure 2 n-butyimercurithiopyridine 5-carboxylic acid.

Aqueous solutions of the various water-soluble salts of the 2n-butylmercuri thiopyridine 5-carboxylic acid resulting from theforegoing procedure may be prepared in manner similar to that alreadydescribed in the case of the Z-ethylmercuri thiopyridine 5-carboxylicacid and may then be employed as antiseptics in water solutions ofsuitable concentrations.

Those skilled in the art will be able, from the general descriptiongiven, and the foregoing specific examples, to produce other mercurycompounds similar or analogous in structure to those herein illustratedand described, and falling within the scope of our invention. Thus incertain cases it may be that amyl or other higher compounds may be usedfor particular purposes, and it is also possible that, under suitablecircumstances, and for particular purposes, the various iso-propyl oriso-butyl compounds may be used instead of the normal compounds.Therefore, While we do not limit our generic claims to the particular orexact compounds described and illustrated above, they are, nevertheless,the best and most suitable compounds for the purpose now known to us,and are, at the present time, the preferred compounds according to ourinvention.

The examples and descriptions herein given are and constitute the bestembodiments of our invention now known to us, but it is to be understoodthat the invention is not necessarily or specifically limited thereto,but may be carried out in other ways without departure from its spiritand within the following claims.

We claim:

1. Alkyl mercuri mercapto compounds of the general formula wherein R. isan alkyl radical and M is a substituent selected from the groupconsisting of hydrogen, alkali metal, alkaline earth metal, ammonium,alkylammonium and alkanolammonium, said compounds being antiseptic andbactericidal and stable toward free oxygen even at elevated temperaturesand in the presence of metal ion catalysts.

2. A water-soluble salt of a compound as defined in claim 1.

3. An alkali-metal salt of a compound as defined in claim 1, such saltbeing water-soluble.

4. An alkylammonium salt of a compound as defined in claim 1, such saltbeing water-soluble.

5. A water-soluble alkanolammonium salt of a compound as defined inclaim 1.

6. An antiseptic and bactericidal compound, soluble in Water and havingthe structural formula:

7. An antiseptic and bactericidal compound, soluble in water and havingthe structural formula:

where R is an alkyl radical.

8. An antiseptic and bactericidal compound, soluble in water and havingthe structural formula:

RUSSEL J. FOSBINDER. LEWIS A. WALTER.

